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Immunologic responses to various forms of allergen immunotherapy
Published in Richard F. Lockey, Dennis K. Ledford, Allergens and Allergen Immunotherapy, 2020
Umit Murat Sahiner, Mohamed H. Shamji, Sakura Sato, Ozge Soyer, Stephen J. Till, Motohiro Ebisawa, Mübeccel Akdis, Stephen R. Durham
AIT results in a rapid inhibition of allergen-challenged late responses, with a slower and proportionately smaller decline in early responses. Biopsies taken from skin and nasal mucosa reveal reductions in inflammatory cell numbers, including mast cells, basophils, and eosinophils. Around 6–8 weeks after starting weekly SCIT, updosing injections, increases occur in allergen-specific IgG, particularly of IgG4 isotype. These antibodies block IgE effector mechanisms including basophil histamine release and IgE-facilitated antigen presentation by dendritic cells (via FcεRI) and B cells (via FcεRII, CD23) to T cells. Induction of allergen-specific IgA is also observed, and these antibodies can induce monocytic cells to produce IL-10, an immunoregulatory cytokine. These humoral responses likely reflect modulation of allergen-specific T-cell responses. Immunotherapy modifies peripheral and mucosal Th2 responses to allergen in favor of Th1 cytokine, IL-10, and/or TGF-β production. Inducible T-regulatory cell (iTregs), in particular, IL-10 (Tr1) and TGF-β (Th3) cells, are detectable within a few weeks of the first injection. IL-10 favors B-cell production of IgG4 and inhibits mast cell, eosinophil, and T-cell responses (Figure 5.1). The mechanism leading to development of these cells has yet to be elucidated, though similar populations can be experimentally induced by tolerogenic dendritic cells (DCs).
CD4+ T Regulatory Cells and Modulation of Undesired Immune Responses
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Rosa Bacchetta, Megan K. Levings, Maria-Grazia Roncarolo
In vivo, production of immunoregulatory cytokines and the differentiation of Tr1 cells is likely controlled by tolerogenic dendritic cells (DC).28,30,31 In the human, at least two types of DC can influence the differentiation of CD4+ T cells: mature myeloid-derived DCs, or DC1, which induce the differentiation of Th1 cells; and lymphoid-derived DCs or DC2, which preferentially give rise to Th2 cells.32 Interestingly, DC2 may also polarise T cells towards IL-10-producing T cells with regulatory activity.33,34 The capacity to drive the differentiation of Tr1 cells may also depend on the maturation state of the DC.35 Immature DC1, which typically express low levels of cytokines and costimulatory molecules, induce a population of CD4+ or CD8+ IL-10-producingT cells with suppressive capacity in vitro.29,36,37 Treatment of DCs with immunomodulatory compounds which reduce or modulate DC maturation, such as vitamin D3 and/or dexamethasone, can also result in reduced T-cell responses and ultimately in the differentiation of Tr1 cells.38,39
Future therapies in lung transplantation
Published in Wickii T. Vigneswaran, Edward R. Garrity, John A. Odell, LUNG Transplantation, 2016
Elizabeth A. Lendermon, John F. McDyer
Dendritic cells are bone marrow–derived professional APCs. That such cells are capable of effecting immune responses has long been understood; now, however, their ability to effect tolerance is also clear. Dendritic cells are quite plastic and can be manipulated to become what are now referred to as tolerogenic dendritic cells. Compelling data in rodent transplant models have demonstrated the ability of tolerogenic dendritic cells generated in vitro to induce donor-specific tolerance. Rapamycin-conditioned host dendritic cells that are pulsed with donor antigen and administered before transplantation prolong cardiac allograft survival indefinitely.63 In addition, dendritic cells that are conditioned with the active form of vitamin D3 and mycophenolate mofetil induce tolerance of pancreatic islet grafts.64 In both these examples, the tolerogenic effects of dendritic cells are associated with induction of regulatory T cells. It is hypothesized that tolerogenic dendritic cells drive regulatory T-cell expansion and that regulatory T cells maintain tolerogenicity in dendritic cells.65 Therefore, dendritic cells also show great promise in translational work directed at induction of tolerance in human transplant patients.
Microbial monotherapy with Prevotella histicola for patients with multiple sclerosis
Published in Expert Review of Neurotherapeutics, 2019
Ashutosh K. Mangalam, Joseph Murray
A current hypothesis in the pathogenesis of MS suggests that peripheral activation of autoreactive T cells with Th1/Th17 phenotypes results in their trafficking into the central nervous system (CNS) where they induce an inflammatory process that leads to increased permeability of the blood–brain barrier and further recruitment of inflammatory cells into CNS [22]. This inflammatory cascade results in demyelination of the CNS, which leads to neurological deficits that are manifested as clinical phenotypes in patients. Therefore, suppression of the initial pro-inflammatory response by immunoregulatory cells (e.g. Tregs, tolerogenic dendritic cells (DCs), regulatory B cells (B-regs), and suppressive macrophages) and/or chemical mediators might ameliorate disease and the associated pathology [23,24]. Oral tolerance studies have suggested that induction of an immune response in the gut can modulate peripheral immune responses [23,24]. Indeed, using a mouse model of MS, administration of P. histicola by oral gavage reduced gut permeability compared to mice treated with media alone or treated with control bacteria, and resulted in disease suppression [15]. This prompted further determination of the ability of immune cells in the gut and periphery to modulate inflammatory immune responses and suppress disease.
CRISPR and personalized Treg therapy: new insights into the treatment of rheumatoid arthritis
Published in Immunopharmacology and Immunotoxicology, 2018
Fatemeh Safari, Safar Farajnia, Maryam Arya, Habib Zarredar, Ava Nasrolahi
In contrast, the broad spectrum of clinical studies about Treg therapy in GVHD, researches on RA are only restricted to animal models. Although in three clinical trials, the therapeutic effect of tolerogenic dendritic cells for RA treatment was evaluated (Clinical Trial.gov)96. Although (RA) is a heterogeneous inflammatory disease with different pathogenesis, various types of spontaneous or induced models of RA showed that Tregs are able to slow down or stop the clinical progression of this disease. For instance, in the collagen-induced arthritis model, in vitro-expanded, polyclonal nTREG cells prevented and almost ceased RA progression97. Also, in another mouse model of RA which induced by proteoglycan as a major component of the joints, LAG3 antigen specific Tregs were able to suppress arthritis98.
Immunomodulatory nano-preparations for rheumatoid arthritis
Published in Drug Delivery, 2023
Chenglong Li, Yangyun Han, Xianjin Luo, Can Qian, Yang Li, Huaiyu Su, Guangshen Du
Fortunately, tolerogenic dendritic cells (DCs) that were successfully produced in vitro have been utilized in clinical studies to restore the function of Tregs in vivo, and these trials originally showed good tolerance and safety (Benham et al., 2015; Bell et al., 2017). However, the clinical translation is prevented by the expense of collecting and expanding autologous cells, complicated technology, and individualization needs, and further research is required to determine its efficacy. Moreover, as an alternative to cell adoptive therapy, in vivo delivery of free antigens and immunomodulators also has limitations. For instance, it is challenging to accomplish by methodically administering free drugs the requirement that the antigen and immunomodulator be taken up by the same cell in order to induce the production of tolerogenic DC or other APCs in vivo (Jiang et al., 2018; Hong et al., 2020); transforming growth factor-β (TGF-β) can directly induce T cell to differentiate into Treg cell (W. Chen et al., 2003), but injection of free form is prone to off-target (McKarns & Schwartz, 2005). To increase safety and effectiveness, it is therefore vital to optimize the targeting and stability of the delivery approach. Immunomodulatory nano-preparations, which have the ability to target and stimulate the growth of tolerogenic APCs (APCs lacking co-stimulatory molecules or secondary signals) or Tregs as well as act as carriers for therapeutic molecules, could be used to achieve this. In this review, we will concentrate on the development of various immunomodulatory nano-preparations for the treatment of RA over the past few years, including fabrication techniques and mechanisms of action (Table 1). Since we are only discussing immunomodulatory nano-preparations based on disease-associated antigens, antigen-independent nanomedicines are not included in this work.